Methods for modeling dosing regimens and the distribution of drugs as a function of time in the body exist and are widely used to aid in the process of optimization of dosing, meaning maximizing drug exposure and efficacy while minimizing safety risks to a patient. FIG. 1 (1) provides a typical two compartment model, often used to simulate the distribution of a drug between two compartments 2, 3 over time, such as the circulation and the GI tract, given the input dose 4 and various transfer rate constants (k12 (5), k21 (6), k10 (7)). In a typical model, a bolus dose of the drug enters the system 4 and the distribution with time is governed by the various transfer rates (k12 (5), k21 (6), k10 (7)). In these models, the rate constants that describe the movement of material between compartments remain constant over time with the transfer rates proportional to the relevant rate constant multiplied by the concentration in a given compartment, and the model predicts how the drug distributes throughout the system as a function of time. Although the two compartment model of FIG. 1 may be used to model the distribution of an administered drug, it is not appropriate for modeling the flow of a target protein, rather than the drug, between two different cellular or extra-cellular compartments under the influence of an administered drug, for several reasons.
First, the transfer rate constants for the protein upon binding to the drug may not remain constant. When a drug, such as a Pharmacological Chaperone, enters the cell its purpose is to bind to the target protein and change the physical properties of the protein, which is expected to change the rate at which the protein is degraded and the rate at which the protein exits the initial binding compartment. Other properties of the protein may also change in the presence of the drug, such as the ability to carry out some reaction. If the target protein is an enzyme, the presence of the drug may affect the ability of the enzyme to catalyze the turnover of particular biological substrates. In order to effectively simulate the effect of the drug on the target protein and its location and activity, a model is needed. The model must be able to handle transfer and degradation rate constants that may change upon binding to the drug, and the model must be capable of simulating the effects of the drug on the system as the drug concentration changes with time.
Second, degradation of the protein can occur from either compartment, not only from the first compartment as in the standard drug distribution model. Third, the activity of the protein in biocompartment two must be captured. The model must be able to calculate the activity of the protein in biocompartment two, as a function of time, in the presence of a certain amount of a substrate and a certain amount of a drug.
The key differences discussed above motivated the creation of a new model that is appropriate for a new type of drug mechanism, and that can simulate the movement and activity of the target protein rather than the drug itself. In addition, software and methods were created to handle various types of user input and to calculate and visualize the computed results. Thus, it is advantageous to provide a new software application that can be used to perform “computational experiments”, test hypotheses, design and test dosing regimens, predict possible outcomes, and to generally provide insight and information relevant to the complex but important process of evaluating and optimizing dosing regimens for drugs that affect the stability, transport, and net activity of the target proteins.